Mild cobalamin deficiency and cognitive function in elderly people Efficacy of oral supplements

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Mild cobalamin deficiency and cognitive

function in elderly people

Efficacy of oral supplements

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Promotoren

Prof. dr. W.A. van Staveren

Hoogleraar Voeding van de Oudere Mens

Afdeling Humane Voeding, Wageningen Universiteit Prof. Dr. W.H.L. Hoefnagels

Hoogleraar Klinische Geriatrie

Kenniscentrum Geriatrie, Radboud Universiteit Nijmegen

Co-promotor

Prof. dr. ir. C.P.G.M. de Groot

Hoogleraar Voedingsfysiologie met bijzondere aandacht voor het Verouderingsproces en de Oudere Mens

Afdeling Humane Voeding, Wageningen Universiteit

Samenstelling promotiecommissie

Prof. dr. P. Van t Veer Wageningen Universiteit Prof. dr. R.G.J. Westendorp Leids Universitair Medisch Centrum Dr. H. van den Berg

Voedingscentrum Dr. A.L. Bjørke Monsen

Haukeland University Hospital, Norway

Dit onderzoek is uitgevoerd binnen de onderzoeksschool VLAG

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Milde vitamine B12 deficiëntie en het

cognitief functioneren van ouderen

De effectiviteit van orale supplementen

Simone Josephina Petra Maria Eussen

Proefschrift

ter verkrijging van de graad van doctor op gezag van de rector magnificus van Wageningen Universiteit, Prof. Dr. M.J. Kropff, in het openbaar te verdedigen op maandag 16 oktober 2006 des namiddags te half twee in de Aula.

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Simone Eussen

Mild cobalamin deficiency and cognitive function in elderly people: efficacy of oral supplements Thesis Wageningen University, The Netherlands - with summaries in English and Dutch

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The truth is rarely pure and never simple (Oscar Wilde)

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ABSTRACT

Cobalamin deficiency is common in older people and has been recognised as a possible cause for several clinical manifestations such as anaemia and cognitive impairment. Markers for cobalamin deficiency include increased concentrations of plasma total homocysteine (tHcy) and methylmalonic acid (MMA), and decreased concentrations of holotranscobalamin (holoTC). Cross sectional analysis in this thesis con-firmed that impaired cognitive performance was associated with relatively unfavourable concentrations of markers for cobalamin status. These results are in line with findings from previous cross-sectional and prospective studies and suggest a role for cobalamin status in cognitive function, in particular because cobalamin deficiency is highly prevalent in old age. According to our recruitment activities it appeared that 26.6% of the older people had mild cobalamin deficiency, which we defined as low to low-normal cobalamin concentrations in combination with increased MMA concentrations. Normalizing mild cobalamin deficiency, defined as a decrease of respectively 80% to 90% of the estimated maximum reduction in plasma MMA concentrations, could be achieved by supplementing daily oral doses of 647 μg to 1032 μg crystalline cobalamin. The main purpose of our research was to investigate whether daily supplementation with such a high dose of oral cobalamin alone or in combination with folic acid has beneficial effects on cognitive function in people aged 70 years or older with mild cobalamin deficiency. We did this in a double-blind, placebo-controlled trial with a relatively large number of carefully se-lected participants, and an extensive assessment of cognitive function. In total, 195 individuals were randomized to receive either 1,000 μg cobalamin, or 1,000 μg cobalamin + 400 μg folic acid, or placebo for 24 weeks. Markers for cobalamin status and cognitive function were assessed before and after 24 weeks of treatment. Assessment of cognitive function included the domains of attention, construction, sensomotor speed, memory and executive function. Cobalamin status did not change in the placebo group, whereas oral cobalamin supplementation corrected mild cobalamin deficiency. Improvement in one domain (memory function) was observed in all treatment groups, and was greater in the placebo group than in the group who received cobalamin alone (P = 0.0036). Oral supplementation with cobala-min alone or in combination with folic acid for 24 weeks was not associated with improvements in other cognitive functions. Blood collection after cessation of oral cobalamin supplementation showed that adequate cobalamin status may maintain for a period of up to 5 months after cessation. Despite the null finding of this trial, recent studies provide clues for future research in improving cognitive function.

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About the author

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Curriculum vitae

Simone Eussen was born on February 13, 1975, in Sittard, the Netherlands. After completing second-ary school in 1995 at the ‘Open Leercentrum’ in Sittard, she studied ‘Human Nutrition’ at Wageningen University. As part of that study, she carried out an internship at ‘TNO Voeding’ in Zeist where she carried out a literature study on functional markers of endothelial function (1998). Her first MSc thesis (1999) was carried out at the ‘Department of Human Nutrition’ in Wageningen in which she studied the relation between trans fatty acids on endothelial function. For her second MSc thesis (2000) she investigated the efficacy of different doses of iodised peanut oil on iodine status of lactating women and their infants in a rural area in Guatemala at the ‘Centre for Studies of Sensory Impairment, Aging and Metabolism’. In November 2000, she received her MSc-degree. The Wageningen University appointed her in 2001 as a PhD-fellow to conduct research on mild cobalamin deficiency and cognitive function in elderly people, as described in this thesis. During this period, she attended several courses and conferences within the framework of the educational program of the graduate school VLAG (Food Technology, Agrobiotechnol-ogy, Nutrition and Health Sciences). Among a number of activities at the ‘Department of Human Nutri-tion’, she was also a member and secretary of the daily board of the committee of temporary scientific staff. In 2005, Simone was selected for the 11th European Nutritional Leadership Programme (ENLP). Currently she continues research on B-vitamins and homocysteine as a post-doc at the Section for Pharmacology, Institute of Medicine, University of Bergen, Norway.

Publications

Full papers

• Effect of oral vitamin B12 with or without folic acid on cognitive performance in elderly people with mild vitamin B12 deficiency: a randomized, placebo-controlled trial. Eussen SJPM, de Groot CPGM, Joosten L, Bloo R, Clarke R, Ueland PM, Schneede J, Blom HJM, Hoefnagels WHL, van Staveren WA. Am J Clin Nutr. 2006; 84(2):361-370

• Effect of supplementation with cobalamin carried either by a milk product or a capsule in mildly cobalamin deficient Dutch elderly people. Dhonukshe-Rutten RAM, van Zutphen M, de Groot LCPGM, Eussen SJPM, Blom HJ, van Staveren WA. Am J Clin Nutr. 2005;82:568-74 • Oral vitamin B12 supplementation in elderly people with mild vitamin B12 deficiency: a

dose-finding trial. Eussen SJPM, de Groot CPGM, Clarke R, Schneede J, Ueland PM, Hoefnagels WHL, van Staveren WA. Arch Intern Med 2005; 165: 1167-71

• Vitamine B12 en cognitieve functies. Eussen SJPM, de Groot LCPGM, Hoefnagels WHL, van Staveren WA. Voeding Nu 2004;(4):29-31 (publication in Dutch)

• Eten tegen het vergeten. Van Staveren WA, Eussen SJPM, de Groot LCPGM. Alzheimer Magazine 2003, 6(4):14-16 (publication in Dutch)

• Five year changes in mental health and associations with vitamin B12/folate status of elderly Europeans. Eussen SJPM, Ferry M, Hiniger I, Haller J, Matthys C, Dirren H. J Nutr Health Aging 2002; 6(1):43-50

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• Changes in Markers of Cobalamin Status after Cessation of Oral B-vitamin Supplements in Elderly People with Mild Cobalamin Deficiency. Eussen SJPM, Ueland PM, Hiddink GJ, Schneede J, Blom HJM, Hoefnagels WHL, van Staveren WA, de Groot CPGM. Submitted

• Cognitive performance in relation to cobalamin and folate status in Dutch elderly people. Eussen SJPM, Joosten L, Bloo R, de Groot CPGM, Clarke R, Ueland PM, Hoefnagels WHL, van Staveren WA. Submitted

• One carbon metabolites in relation to cognitive performance in Dutch elderly people. Eussen SJPM, Ueland PM, Clarke R, Blom HJM, Hoefnagels WHL, van Staveren WA, de Groot CPGM. Submitted

Abstracts

• Effect of daily oral vitamin B12 and vitamin B12/folate supplementation on cognitive

performance in elderly people with vitamin B12 deficiency: a randomized placebo controlled trial. Eussen SJPM, de Groot CPGM, Joosten L, Bloo R, Clarke R, Ueland PM, Schneede J, Blom HJM, Hoefnagels WHL, van Staveren WA. Haematologica Reports 2005; 1(3):49 and J Nutr. Health and Aging 2005; 9(3):148

• Minimum effective dose of oral vitamin B12 to treat elderly people with vitamin B12 deficiency. Eussen SJPM, de Groot CPGM, Clarke R, Schneede J, Ueland PM, Hoefnagels WHL, van Staveren WA. Journal of Nutrition, Health and Aging 2003; 7(4):210

• The supplementation of iodized oil to lactating rural Guatemalan women improves their childs iodine status. Bulux J, Eussen SJPM, Harbers MM, de Mutsert R, Romero-Abal ME, West CE, Solomons NW. Ann Nutr Metab 2001;45(suppl 1):38

• Efficacy of different doses of iodized peanut oil on iodine status of lactating women and their infants in a rural mountainous area in Guatemala. Eussen SJPM, Harbers MM, de Mutsert R, West CE, van der Heide D, Bulux J, Romero-Abal ME, Solomons NW. Ann Nutr Metab

2001;45(suppl 1):40 (Abstract)

Training and supervision plan

Discipline specific activities

• Meetings “International Academy Nutrition and Aging (IANA)”; Chicago (USA, 2006), Toulouse (France, 2004), and Albuquerque (USA, 2003)

• Meetings NWO Nutrition; Arnhem (NL), 2001, 2004 and 2005

• International Conferences “Homocysteine Metabolism”; Milan (Italy, 2005), and Saarbruecken (Germany, 2005)

• Annual Vitamin Meetings of the Homocysteine LOCUS Norway; Noordwijkerhout (NL, 2005) and Londonderry (Northern Ireland, 2004)

• Symposium “En ook nog dement”; Nijmegen (NL), 2004

• Masterclass Geriatric Nutrition: “Diet, functionality and disease”; Wageningen (NL), 2004

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• Symposium “Add years to life: Nutrition Matters”; Wageningen (NL), 2004

• Conference “FASEB Folic acid, vitamin B12 & one carbon metabolism”; Snowmass (USA), 2002 and 2004

• ZON Implementatiedagen; The Hague (NL), 2003

• Twelfth Alzheimer Europe Conference; Maastricht (NL), 2002 • Symposium “Senioren en Voeding”; Wageningen (NL), 2002

• Symposium “Homocysteine, folate and vitamin B12 in cardiovascular and neurological diseases”; UMC St Radboud, Ravenstein (NL), 2001

• SENECA-HALE meeting; Wageningen (NL), 2001

• Seventeenth International Congress on Nutrition (IUNS); Vienna, 2001

• “Nutrition and Lifestyle Epidemiology”; VLAG advanced course, Wageningen (NL), 2001 • Symposium on Geriatric topics; Arnhem (NL), 2001

General courses

• Talent Classes “Media training” and “Subsidies”; NWO, The Hague (NL), 2005 • Course “Mixed Models and missing data”; Brussels (B), 2005

• Good Clinical Practise, NUTRIM, Maastricht (NL), 2005

• European Nutritional Leadership Programme (ENLP), Luxembourg (L), 2005 • Course “Cognitive Neuropsychology”, Utrecht (NL), 2003

• Written English and Scientific Writing courses, Wageningen University, (NL), 2003 • Epidemiologic data analysis by K. Rothman; Bilthoven (NL), 2002

• Systematic literature research; NUTRIM, Maasticht (NL), 2001 • VLAG PhD week, Bilthoven (NL), 2001

• Organizing and supervising thesis work, Wageningen University (NL), 2001

Optional courses and activities

• Oldsmobiles, Wageningen University, 2001-2006 • Homocysteine Club, Wageningen University, 2001-2005 • Journal Club, Wageningen University, 2001-2004

• PhD study tour to Switzerland, Italy, Germany, and the United Kingdom, Wageningen University, 2001 and 2005

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COLOFON

The studies described in this thesis were supported by grant 2100.0067 from the Netherlands Organization for Health Research and Development (ZON-MW), the Hague, the Netherlands; grant 001-2002 from Kellogg’s Benelux, Zaventem, Belgium; grant 2004-E2 from the Nutricia Health Foundation, Wageningen, The Netherlands; grant 20041227102004 from the Dutch Dairy Association (NZO), Zoetermeer, the Netherlands; and grant QLK3-CT-2002-01775 from the Foundation to Promote Research Into Functional Vitamin B12 Deficiency and the European Union BIOMED Demonstration Project.

The author gratefully acknowledges financial support for the printing of this thesis by Wageningen University, DSM Nutritional products Ltd, Nutricia Nederland BV, and the Dutch Association for Gerontology (NVG).

Lay-out thesis: Rob Gros, Studio Pothoff, Veenendaal Printing: Ponsen en Looijen, Wageningen